CN108165486B - Experimental system and method suitable for precise regulation and control of macromolecule crystallization process - Google Patents
Experimental system and method suitable for precise regulation and control of macromolecule crystallization process Download PDFInfo
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- C12M—APPARATUS FOR ENZYMOLOGY OR MICROBIOLOGY; APPARATUS FOR CULTURING MICROORGANISMS FOR PRODUCING BIOMASS, FOR GROWING CELLS OR FOR OBTAINING FERMENTATION OR METABOLIC PRODUCTS, i.e. BIOREACTORS OR FERMENTERS
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- C12M41/00—Means for regulation, monitoring, measurement or control, e.g. flow regulation
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- C12M41/00—Means for regulation, monitoring, measurement or control, e.g. flow regulation
- C12M41/30—Means for regulation, monitoring, measurement or control, e.g. flow regulation of concentration
- C12M41/34—Means for regulation, monitoring, measurement or control, e.g. flow regulation of concentration of gas
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- C12N9/00—Enzymes; Proenzymes; Compositions thereof; Processes for preparing, activating, inhibiting, separating or purifying enzymes
- C12N9/14—Hydrolases (3)
- C12N9/24—Hydrolases (3) acting on glycosyl compounds (3.2)
- C12N9/2402—Hydrolases (3) acting on glycosyl compounds (3.2) hydrolysing O- and S- glycosyl compounds (3.2.1)
- C12N9/2462—Lysozyme (3.2.1.17)
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- C12N9/00—Enzymes; Proenzymes; Compositions thereof; Processes for preparing, activating, inhibiting, separating or purifying enzymes
- C12N9/98—Preparation of granular or free-flowing enzyme compositions
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- C12Y302/00—Hydrolases acting on glycosyl compounds, i.e. glycosylases (3.2)
- C12Y302/01—Glycosidases, i.e. enzymes hydrolysing O- and S-glycosyl compounds (3.2.1)
- C12Y302/01017—Lysozyme (3.2.1.17)
Abstract
The invention belongs to the technical field of crystallization, and relates to an experimental system and method suitable for precise regulation and control of a macromolecule crystallization process. The system is a closed space under normal pressure and mainly comprises a platform arrangement horizontal moving groove, a special backwashing module for a flow channel, a liquid drop dripping control module, an observation module, a computer system for user observation and an experimental condition control module. The invention utilizes the high-precision movable knobs of the X-axis platform and the Y-axis platform of the system and the precise position control of the needle head to ensure that macromolecular solution can be dripped to the correct position of the bulge or the recess and ensure the crystal crystallization microcosmic environment and the precise operation of later crystal backwashing; the crystallization induction period of the target crystal form is measured through real-time data of a high-power camera, the culture environment of the crystal is adjusted in real time according to experimental conditions, and the crystallization efficiency and the success rate are improved. The method is simple and easy to implement, has high yield, can be suitable for repeated conventional experiments, and can also be explored by utilizing the limit crystallization condition.
Description
Technical Field
The invention belongs to the technical field of crystallization, and relates to an experimental system and method suitable for precise regulation and control of a macromolecule crystallization process.
Background
The increasing demand of drugs mainly comprising macromolecular drugs promotes the development of the crystals of the related macromolecular drugs. From the discovery of the effect of macromolecular drugs on the design of drug structures, stable production flow design and preparation process development have become important research directions on commercialization of new drugs. The crystallization process of the macromolecular drug is the key point of the production flow design, the target crystal form of the drug is regulated and controlled, the crystallization induction period is shortened, and the cost and the production feasibility in the drug preparation process are greatly influenced by related researches such as large-batch preparation of the crystals. Because pathogens mutate faster and become more adaptive to drugs, frequent drug updates are required to cope with the mutated pathogens. Therefore, a large amount of target crystals need to be prepared, and the characteristics of the crystal system such as crystal form, granularity, morphology, purity and the like are ensured through a precisely controlled preparation process. The development of experimental systems and methods for precisely regulating and controlling the macromolecule crystallization process by taking the method as a target is also very important. CN 103254274a discloses a regulation and optimization device for protein crystals, which is used to determine whether a substance in a crystalline state is a target protein. However, the method is not universal and has no significant significance for industrial production and control because the method is limited to biomacromolecules capable of analyzing structures by using an X single crystal diffraction technology. At present, relevant devices for precise regulation and control research and crystallization observation of the universal macromolecular crystal are not reported in documents.
Researches show that the regulation and control of crystal forms of the macromolecular crystals in the limited space can be accurately improved due to the limiting effect of the surrounding environment, the target crystals are obtained, and meanwhile, the shape of the limited space has a positive effect on the regulation and control of crystal growth crystal faces. The conclusion can be popularized to biomacromolecules and can also solve the problem of the crystallization process of macromolecular drugs. However, the limited space is not favorable for crystal form observation, crystal induction period measurement, crystal extraction and the like related to a crystallization system. Therefore, the conventional experiment system and monitoring method need to be improved, and a crystallization experiment system integrating observation, environment control and accurate sample injection is needed. The experimental system needs to meet the condition of accurately dripping the liquid drops of the target system; meanwhile, the domain-limited structure of the high-precision micron-scale crystallization platform can be any regular graph, and the high-precision moving mechanism of the x-axis platform and the y-axis platform of the system and the accurate position control of the needle head are utilized to ensure that macromolecular solution can be dripped to the convex or concave correct position and ensure the precise operation of crystal crystallization micro-environment and later-stage crystal backwashing. In addition, the target crystal form is conveniently and timely screened and regulated in the experimental process, the crystal is observed, the crystallization induction period of the target crystal form is measured through real-time data of a high-power camera, the culture environment of the crystal is adjusted in real time according to the experimental condition, and the crystallization efficiency and the success rate are improved.
Disclosure of Invention
The invention mainly designs an experimental system for providing a crystal culture environment for high-precision macromolecular crystals, controlling the dropping position of liquid drops, observing the growth process of the crystals and screening the crystals, and the system can quantitatively drop a target macromolecular solution and observe the actual growth condition of the crystals in real time.
The technical scheme of the invention is as follows:
an experimental system suitable for accurate regulation and control of a macromolecule crystallization process is a closed space surrounded by a shell 1 under normal pressure and mainly comprises a platform arrangement horizontal moving groove, a special backwashing module I for a runner, a liquid drop dripping control module II, an observation module III, a computer system IV for user observation and an experimental condition control module V; the platform arrangement horizontal moving groove and special backwashing module I for the runner, the droplet dripping control module II, the observation module III and the experimental condition control module V are positioned in the closed space, and the computer system IV for user observation is positioned outside the closed space;
the platform arrangement horizontal moving groove and flow channel special backwashing module I comprises a platform horizontal moving groove 2, an x-axis horizontal adjusting mechanism 3, a y-axis horizontal adjusting mechanism 4 and a high-flux macromolecular crystallization culture platform 5; the high-flux macromolecular crystal culture platform 5 is arranged on the platform horizontal moving groove 2, the platform horizontal moving groove 2 adjusts the horizontal position through the x-axis horizontal adjusting mechanism 3, and adjusts the vertical height through the y-axis horizontal adjusting mechanism 4, so that the high-flux macromolecular crystal culture platform 5 can accurately move;
the liquid drop dripping control module II comprises a sample injector 6, a piston pushing and adjusting mechanism 7 and a sample injector height adjusting mechanism 8, wherein the piston pushing and adjusting mechanism 7 is used for accurately dripping the liquid drop volume of the sample injector 6, and the sample injector height adjusting mechanism 8 is used for controlling the position of the sample injector 6;
the observation module III comprises a high-power camera 9 and a camera adjusting unit 11, the high-power camera 9 is fixed on the camera adjusting unit 11, and the state of the crystal inside the liquid drop on the high-flux macromolecular crystal culture platform 5 is observed by controlling the angle, the brightness and the magnification of the high-power camera 9;
the experimental condition control module V comprises a temperature and humidity measuring and controlling device 13 for regulating and controlling the humidity and the temperature required in the closed space;
the computer system IV for user observation comprises a data leading-out wire 10 and a user observation computer 12, and is used as an external extension of the observation system so as to facilitate a user to observe the crystal growth condition under the lens of the high-power camera 9 by utilizing computer software; the user observation computer 12 is connected with the camera adjusting unit 11 through the data leading-out wire 10;
the high-flux macromolecular crystal culture platform 5 comprises a backwash liquid inlet 14, a backwash liquid flow passage 15 and a backwash liquid outlet 16, wherein backwash liquid enters from the backwash liquid inlet 14, and flows out from the backwash liquid outlet 16 after the backwash liquid washes crystals in the backwash liquid flow passage 15.
The backwash liquid flow passage 15 is a micron-sized structure with a convex or concave structure in a regular pattern.
The temperature and humidity measuring and controlling device 13 has a humidity control range of 10-100% and a temperature control range of-50-200 ℃.
The X-axis horizontal adjusting mechanism 3, the Y-axis horizontal adjusting mechanism 4 and the sampler height adjusting mechanism 8 are all in error per one thousandth of 25.4 mm.
The high-power camera 9 has a magnification of 10-600 times.
An experimental method suitable for precise regulation and control of a macromolecule crystallization process comprises the following steps:
(1) adding the prepared crystal culture solution into an injector 6, placing a high-flux macromolecular crystallization culture platform 5 on a platform horizontal moving groove 2, and completing the preparation work before crystal culture;
(2) adjusting the temperature and humidity measuring and controlling device 13 to make the temperature and humidity conditions in the closed space reach the set values in the crystallization process, wherein the temperature and humidity in the whole experiment process are controlled by an experiment condition control module V;
(3) in the experiment process, the x-axis horizontal adjusting mechanism 3 and the y-axis horizontal adjusting mechanism 4 are adjusted, a target site on the high-flux macromolecular crystal culture platform 5, to which liquid drops are dripped, is aligned to the sample injector 6, the height adjusting mechanism 8 of the sample injector is adjusted according to the height of the high-flux macromolecular crystal culture platform 5, the piston pushing mechanism 7 is rotated to extrude the liquid drops after the preparation is carried out, and the volume of the liquid drops is given through scales on the sample injector 6;
(4) observing the state of the crystal liquid drop by using a high-power camera 9 of an observation module III, converting the observed content into an electric signal, displaying the electric signal on a user observation computer 12 through a data lead-out wire 10, and collecting and storing a crystal state picture or video;
(5) when the crystal culture is finished, taking the high-flux macromolecular crystal culture platform 5 out of the platform horizontal moving groove 2, connecting a pipeline of an antisolvent to an antiscour liquid inlet 14, starting washing, enabling a washing liquid to pass through an antiscour liquid flow passage 15, collecting the washing liquid at an antiscour liquid outlet 16, backwashing the crystal, and finishing the operation of the high-flux crystal culture.
The invention has the beneficial effects that: by utilizing a high-precision moving mechanism of an x-axis platform and a y-axis platform of the system and the precise position control of a needle head, the macromolecule solution can be ensured to be dripped to a convex or concave correct position, and the crystal crystallization micro environment and the precise operation of later crystal backwashing can be ensured; the crystallization induction period of the target crystal form is measured through real-time data of a high-power camera, the culture environment of the crystal is adjusted in real time according to experimental conditions, and the crystallization efficiency and the success rate are improved.
Drawings
FIG. 1 is a schematic side view of the present system.
FIG. 2 is a schematic, enlarged partial view of the high throughput macromolecular crystallization culture platform of the present system.
FIG. 3 is a top view of four crystal growth platform designs suitable for use with the present system.
In fig. 3: each graph is a part of a high-precision crystallization platform, and the characteristic dimension of each structure is 0.01-0.5 mm, wherein (1) the graph is of a square structure, (2) the graph is of a round structure, (3) the graph is of a hexagonal structure, (4) and the graph is of a diamond structure; each feature may be either a raised or a recessed feature, as desired.
In fig. 1: 1, a shell; 2, a platform horizontal moving groove; a 3 x-axis horizontal adjustment mechanism;
4 y-axis horizontal adjustment mechanism; 5, a high-flux macromolecular crystallization culture platform; 6, a sample injector;
7, a piston propulsion adjusting mechanism; 8, a sample injector height adjusting mechanism; 9 high power camera;
10 data lead-out lines; 11 a camera adjusting unit; 12 the user observes the computer;
13 a temperature and humidity measuring and controlling device; 14 a backwash liquid inlet; 15 backwash liquid flow path;
16 backwash liquid outlet; i, arranging a horizontal moving groove and a special backwashing module for a flow channel on a platform;
II, a liquid drop dripping control module; III, observing the module; IV, observing a computer system by a user;
and V, an experiment condition control module.
Detailed Description
The following further describes a specific embodiment of the present invention with reference to the drawings and technical solutions.
The case of lysozyme crystal culture illustrates the use method of the invention in detail.
Preparing a lysozyme crystal culture solution, putting the prepared lysozyme crystal culture solution into a sample injector 6 for later use, and putting a high-flux macromolecular crystal culture platform 5 on a platform horizontal moving groove 2 to finish the preparation work before crystal culture;
adjusting a temperature and humidity measuring and controlling device 13 to enable the temperature and humidity conditions in the closed space shell 1 to reach the set values in the lysozyme crystallization process, wherein the temperature and humidity in the whole experiment process are controlled by an experiment condition control module V;
in the experiment process, the x-axis horizontal adjusting mechanism 3 and the y-axis horizontal adjusting mechanism 4 are adjusted, a target site on the platform, on which liquid drops are dripped, is aligned with the sample injector 6, the height adjusting mechanism 8 of the sample injector is adjusted according to the height of the high-flux macromolecular crystal culture platform 5, the piston propelling mechanism 7 is rotated to extrude the liquid drops after the preparation is ready, and the volume of the liquid drops is given by scales on the sample injector 6;
observing the state of the crystal liquid drop by using a high-power camera 9 of an observation module III, converting the observed content into an electric signal, displaying the electric signal on a user observation computer 12 through a data lead-out wire 10, and collecting and storing a crystal state picture or video;
when the lysozyme crystal is cultured, the high-flux macromolecular crystal culture platform 5 is taken out from the platform horizontal moving groove 2, the pipeline of the anti-solvent is connected with the inlet 14 of the anti-washing liquid, the anti-washing liquid starts to be washed, the washing liquid passes through the flow passage 15 of the anti-washing liquid and is collected at the outlet 16 of the anti-washing liquid, the crystal is backwashed, and the operation of the high-flux crystal culture is completed.
The method is simple and easy to implement, has high yield, can be suitable for repeated routine experiments, and can also be explored under the limit crystallization condition. The above description is only for the purpose of illustrating the present invention and is not to be construed as limiting the invention, and equivalents, modifications and apparatus improvements, etc., which are similar to the above description are intended to be included within the scope of the present invention.
Claims (9)
1. An experimental system suitable for accurate regulation and control of a macromolecule crystallization process is characterized in that the experimental system is a closed space surrounded by a shell (1) under normal pressure and mainly comprises a platform arrangement horizontal moving groove, a special backwashing module (I) for a runner, a droplet dripping control module (II), an observation module (III), a computer system (IV) for user observation and an experimental condition control module (V); the platform is provided with a horizontal moving groove, a backwashing module (I) special for a flow channel, a liquid drop dripping control module (II), an observation module III and an experimental condition control module (V) which are positioned in the closed space, and a computer system (IV) for user observation is positioned outside the closed space;
the platform arrangement horizontal moving groove and flow channel special backwashing module (I) comprises a platform horizontal moving groove (2), an x-axis horizontal adjusting mechanism (3), a y-axis horizontal adjusting mechanism (4) and a high-flux macromolecular crystallization culture platform (5); the high-flux macromolecular crystal culture platform (5) is arranged on the platform horizontal moving groove (2), the platform horizontal moving groove (2) adjusts the horizontal position through the x-axis horizontal adjusting mechanism (3), and adjusts the vertical height through the y-axis horizontal adjusting mechanism (4), so that the high-flux macromolecular crystal culture platform (5) can accurately move;
the liquid drop dripping control module (II) comprises a sample injector (6), a piston pushing and adjusting mechanism (7) and a sample injector height adjusting mechanism (8), wherein the piston pushing and adjusting mechanism (7) is used for accurately dripping the liquid drop volume of the sample injector (6), and the sample injector height adjusting mechanism (8) is used for controlling the position of the sample injector (6);
the observation module III comprises a high-power camera (9) and a camera adjusting unit (11), the high-power camera (9) is fixed on the camera adjusting unit (11), and the state of the crystal in the liquid drop on the high-flux macromolecular crystal culture platform (5) is observed by controlling the angle, the brightness and the magnification of the high-power camera (9);
the experimental condition control module (V) comprises a temperature and humidity measuring and controlling device (13) for regulating and controlling the humidity and the temperature required in the closed space;
the computer system (IV) for user observation comprises a data lead-out wire (10) and a user observation computer (12) which is used as an external extension of the observation system so as to facilitate a user to observe the crystal growth condition under the lens of the high-power camera (9) by utilizing computer software; the user observation computer (12) is connected with the camera adjusting unit (11) through the data leading-out wire (10);
the high-flux macromolecular crystal culture platform (5) comprises a backwash liquid inlet (14), a backwash liquid flow passage (15) and a backwash liquid outlet (16), wherein backwash liquid enters from the backwash liquid inlet (14), and after the backwash liquid washes crystals in the backwash liquid flow passage (15), the backwash liquid flows out from the backwash liquid outlet (16).
2. The experimental system for precisely regulating the crystallization process of macromolecules as claimed in claim 1, wherein the backwash liquid flow channel (15) is a regular pattern of convex or concave structures with micron-scale structures.
3. The experiment system suitable for precise regulation and control of the macromolecule crystallization process according to claim 1 or 2, wherein the temperature and humidity measurement and control device (13) has a humidity control range of 10% to 100% and a temperature control range of-50 ℃ to 200 ℃.
4. The experimental system suitable for the precise regulation and control of the macromolecule crystallization process according to claim 1 or 2, characterized in that the x-axis horizontal adjustment mechanism (3), the y-axis horizontal adjustment mechanism (4) and the injector height adjustment mechanism (8) have errors of one thousandth of an error of every 25.4 mm.
5. The experimental system suitable for the precise regulation and control of the macromolecule crystallization process according to claim 3, wherein the x-axis horizontal adjusting mechanism (3), the y-axis horizontal adjusting mechanism (4) and the injector height adjusting mechanism (8) have errors of one thousandth of an error of every 25.4 mm.
6. The experimental system suitable for precise regulation and control of the macromolecule crystallization process according to claim 1, 2 or 5, wherein the high power camera (9) has a magnification of 10-600 times.
7. The experimental system suitable for precise regulation and control of the macromolecule crystallization process according to claim 3, wherein the high power camera (9) has a magnification of 10-600 times.
8. The experimental system suitable for precise regulation and control of the macromolecule crystallization process according to claim 4, wherein the high power camera (9) has a magnification of 10-600 times.
9. An experimental method using the experimental system for precise control of the crystallization process of macromolecules of claim 1, comprising the steps of:
(1) adding the prepared crystal culture solution into a sample injector (6), and placing a high-flux macromolecular crystal culture platform (5) on a platform horizontal moving groove (2) to finish the preparation work before crystal culture;
(2) adjusting a temperature and humidity measuring and controlling device (13) to enable the temperature and humidity conditions in the closed space to reach the set values in the crystallization process, wherein the temperature and humidity in the whole experiment process are controlled by an experiment condition control module (V);
(3) in the experimental process, the x-axis horizontal adjusting mechanism (3) and the y-axis horizontal adjusting mechanism (4) are adjusted, the target site of the dropwise adding liquid drops on the high-flux macromolecular crystal culture platform (5) is aligned to the sample injector (6), the height adjusting mechanism (8) of the sample injector is adjusted according to the height of the high-flux macromolecular crystal culture platform (5), the liquid drops are extruded by rotating the piston pushing mechanism (7) after the sample injector is ready, and the volume of the liquid drops is given out through scales on the sample injector (6);
(4) observing the state of the crystal liquid drop by using a high-power camera (9) of an observation module (III), converting the observed content into an electric signal, displaying the electric signal on a user observation computer (12) through a data lead-out wire (10), and collecting and storing a crystal state picture or video;
(5) when the crystal culture is finished, taking the high-flux macromolecular crystal culture platform (5) out of the platform horizontal moving groove (2), connecting a pipeline of a back solvent to a backwash liquid inlet (14), starting washing, collecting the washing liquid through a backwash liquid flow passage (15) at a backwash liquid outlet (16), and backwashing the crystal to finish the operation of the high-flux crystal culture.
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| CN201711443611.3A CN108165486B (en) | 2017-12-27 | 2017-12-27 | Experimental system and method suitable for precise regulation and control of macromolecule crystallization process |
| PCT/CN2018/121637 WO2019128766A1 (en) | 2017-12-27 | 2018-12-18 | Experimental system and method applicable to precise regulation of macromolecular crystallization processes |
| US16/349,572 US11452948B2 (en) | 2017-12-27 | 2018-12-18 | Experiment system and method for accurate controlling of macromolecular crystallization process |
| EP18871811.8A EP3530726A4 (en) | 2017-12-27 | 2018-12-18 | Experimental system and method applicable to precise regulation of macromolecular crystallization processes |
| JP2019551564A JP6742624B2 (en) | 2017-12-27 | 2018-12-18 | Experimental system and method applied to precise adjustment and control of large molecule crystallization process |
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| JP6742624B2 (en) | 2017-12-27 | 2020-08-19 | 大連理工大学 | Experimental system and method applied to precise adjustment and control of large molecule crystallization process |
| CN109794078A (en) * | 2019-03-21 | 2019-05-24 | 大连理工大学 | A kind of method and system of the automatic nucleus screening of membrane interface regulation |
| CN111139517A (en) * | 2020-01-03 | 2020-05-12 | 浙江工业大学 | Preparation method and device of array type liquid drop crystal |
| CN111494979B (en) * | 2020-04-08 | 2021-07-16 | 大连理工大学 | Crystallization system and method for strengthening molecular crystallization process |
| CN114470851A (en) * | 2022-01-20 | 2022-05-13 | 大连理工大学 | Bionic system and method for in-vitro regulation and control of inorganic salt crystallization |
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| CN101440513A (en) * | 2008-12-05 | 2009-05-27 | 青岛大学 | Microscopic real-time visual crystal growth apparatus by solution method |
| WO2013191173A1 (en) * | 2012-06-18 | 2013-12-27 | 独立行政法人理化学研究所 | Sample dispensing apparatus, crystallization method for protein, and microplate formation sheet |
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| WO2003053998A1 (en) * | 2001-12-11 | 2003-07-03 | Mitsubishi Rayon Co., Ltd. | Array for crystallizing protein, device for crystallizing protein and method of screening protein crystallization using the same |
| US7763471B2 (en) * | 2006-04-18 | 2010-07-27 | Advanced Liquid Logic, Inc. | Method of electrowetting droplet operations for protein crystallization |
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| CN101440513A (en) * | 2008-12-05 | 2009-05-27 | 青岛大学 | Microscopic real-time visual crystal growth apparatus by solution method |
| WO2013191173A1 (en) * | 2012-06-18 | 2013-12-27 | 独立行政法人理化学研究所 | Sample dispensing apparatus, crystallization method for protein, and microplate formation sheet |
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